Peritoneal carcinomatosis is a fatal form of metastasis that occurs when intra-abdominal cancers invade into the peritoneal cavity and attach to the peritoneum, a resilient tissue lining the abdominal cavity and its internal organs. Peritoneal carcinomatosis can also occur following surgical resections of intra-abdominal cancers, which releases cancer cells, blood, and lymph into the peritoneal cavity. In patients with gastric cancers, the peritoneum and liver are the major sites of recurrence following extended lymphadenectomy (Maruyama et al. World J Surg 1987, 11: 418-25; Kaibara et al. Am J Surg 1990, 159: 218-21; Korenaga et al. Surg Gynecol Obstet 1992, 174: 387-93). Following resection of ovarian cancers, the most frequent site of recurrence is the peritoneal cavity (Armstrong et al. NEJM 2006, 354: 34-43).
Locoregional recurrence within the abdominal cavity is the first site of recurrence following resection of gastric cancers in approximately 50% of patients (Sugarbaker et al. Seminars in Surgical Oncology 2003, 21: 233-248). The evidence that intra-abdominal locoregional recurrence impacts patient survival comes from multiple studies showing that the recurrent gastric cancers remain confined to the abdominal cavity even at the time of death in many cases (Gunderson et al. Int J Radiat Oncol Biol Phys 1992, 8: 1-11; Wisbeck et al. Radiother Oncol 1986, 7: 13-18; Landry et al. Int J Radiat Oncol Biol Phys 1990: 1357-1362).
Other intra-abdominal malignancies, notably pseudomyxoma peritonei, appendiceal carcinoma, and mesothelioma, commonly result in peritoneal carcinomatosis as well.
The hallmarks of cancer are invasion and metastasis. Metastasis occurs most commonly when cancer cells gain entrance into the lymphatic or hematogenous vessels through which they travel and then exit within capillary beds in secondary tissues. The rate-limiting step in metastasis is when circulating cancer cells re-adhere to tissues in secondary sites. It is well known that patients with advanced cancers often have high levels of circulating cancer cells. During surgical resections of advanced malignancies, there is often a transient increase in circulating cancer cells as well. High levels of circulating cancer cells portend poorer survival due to the metastatic potential of the circulating cells.
Most women who undergo resection of ovarian cancer experience recurrence in the peritoneal cavity with systemic dissemination much less commonly. A recent large randomized trial comparing intravenous and intraperitoneal paclitaxel (total of 6 cycles every 3 weeks) in women with stage III ovarian cancer showed an increase in long-term survival of 15.9 months for women who received intraperitoneal chemotherapy (Armstrong et al. New England Journal of Medicine 2006, 354: 34-43). This improvement in survival occurred despite the fact that only 42% of patients completed all 6 cycles of chemotherapy. These results led the NCI to declare intraperitoneal therapy as the recommended management strategy for optimally debulked ovarian cancer.
As such, improved and more effective compounds and methods for the treatment and prevention of peritoneal carcinomatosis are needed.
International Publication Number WO 2009/124272 A2 discloses methods of inhibiting proliferation of cancer cells, readhesion of cancer cells and other methods employing inhibitors of NF-κB and activators of JNK, along with compounds useful therefor.